Digestion is the physiological process by which ingested food is broken down into readily absorbed nutrient components, including vitamins and trace elements. Following ingestion, food passes through various segments of the gastrointestinal (GI) tract and digestion is carried out, primarily by digestive enzymes. Three groups of digestive enzymes essential to this process include proteases (for protein digestion), lipases (for fat digestion) and amylases (for carbohydrate digestion).
Food digestion and nutrient absorption occur in the small intestine. There, ingested food is broken down by digestive enzymes for ready absorption. Most digestive enzymes are secreted by the pancreas and arrive in the small intestine through the pancreatic duct.
The observation in the early 1970's that trypsin inhibitors placed into the rat upper small intestine stimulated pancreatic enzyme secretion, led to the understanding that trypsin and chymotrypsin are critical for controlling digestive enzyme secretion by the pancreas (G. M. Green and R. L. Lyman, Proc. Soc. Exp. Biol. Med. 140, 6-12 (1972)). Similarly, removal or diversion of bile and pancreatic juice from the upper small intestine was also observed to stimulate pancreatic enzyme secretion. These data suggested the following negative feedback mechanism: the stimulation of pancreatic enzyme secretion is controlled by the level of trypsin activity within the lumen of the small intestine.
In cases of pancreatic insufficiency, the pancreas fails to produce and/or secrete sufficient amounts of digestive enzymes to support normal digestive processes. This failure typically leads to maldigestion, which in turn leads to malabsorption. Pancreatic insufficiency manifests itself in diseases, such as pancreatitis (both acute and chronic forms) and cystic fibrosis, and in some post-operative GI surgeries.
Chronic and acute pancreatitis are diseases characterized by fibrosis and irreversible loss of pancreatic exocrine function. The diseases are also characterized by release and activation of digestive enzymes within the pancreas, leading to autodigestion of the organ itself. While some patients are treated by surgical removal of the parathyroid glands, chronic pancreatitis is largely an untreatable disease worldwide (S. Sidhu and R. K. Tandon, Postgrad. Med. J. 72, 327-333 (1996)). The incidence rate for this disease in the United States alone is over 100,000 people each year (Digestive Disease Statistics, NIDDK, 2003).
To date, therapy for pancreatic insufficiency is primarily based on orally-administered porcine pancreatic enzyme extract preparations containing lipase, protease and amylase components. Such enzyme preparations typically include high levels of lipase for treatment of steatorrhea (excretion of fat, due to fat maldigestion/maladsorption); whereas high protease levels are generally thought to be more effective in treating azotorrhea (excretion of protein, due to protein maldigestion/maladsorption). For several reasons, such pancreatic extracts have had limited success for treatment of abdominal pain. Proteases make up only a relatively small proportion of such extracts and within that fraction, a smaller still amount of trypsin.
The mechanism responsible for pain in pancreatic insufficiency patients remains poorly understood (J. Mossner, Acute and Chronic Pancreatis 79, 861 (1999); N. J. Greenberger, Gastroenterol Clin North Am. 28, 687 (1999)).
One proposed mechanism underlying pain, including abdominal pain, is linked to induction of cholecystokinin (hereinafter “CCK”), a peptide that is released by the mucosal epithelial cells of the duodenum and the enteric nervous system and regulates digestion of nutrients. It has been shown that an increase in CCK stimulates the release of destructive enzymes from the pancreas. The release of CCK from epithelial cells is modulated by the secretion of two other peptides, a monitor peptide and an intestinal CCK releasing factor (CCK-RF), that interact with specific endocrine cell surface receptors (R. A. Liddle, American Physiological Society, G319-G327 (1995)). Intraluminal trypsin, which can degrade both of these peptides, inhibits the release of CCK and consequently inhibits pancreatic enzyme secretion. The opposite effect is achieved if trypsin inhibitors and foods are present to serve as trypsin-binding substrates. As a result, a sustained increase in CCK causes a continuous stimulation of pancreatic enzyme production, which in turn may cause pain. Based on this mechanism, one proposed treatment for chronic pancreatitis and its associated pain seeks to control CCK levels using an emulsion containing mixed length polypeptides and a medium chain triglyceride (PCT patent application WO 98/36734).
Although pain reduction has been reported with porcine pancreatic enzyme substitution therapy, the role of proteases generally to treat pain remains unclear. For example, one study demonstrates that intraduodenal perfusion with pancreatic proteases, trypsin and chymotrypsin, but not with amylases or lipases, suppresses pancreatic exocrine secretion in patients suffering from chronic pancreatitis (J. Slaff et al., Gastroenterology 87, 44-52 (1984). Other studies report that such pancreatic proteases are not the primary factor in pain reduction but that they instead act synergistically with lipase and amylase components to that end (G. Isaksson and I. Ihse. Dig. Dis. Sci. 28, 97-102.(1983); J. Slaff et al. Gastroenterology 87, 44-52 (1983)). In contrast, other studies report no amelioration of pain following pancreatic protease or extract treatments (H. Halgreen et al. Scand. J. Gastroenterol. 21, 104-108 (1986); J. Mössner et al., Digestion 53, 54-66 (1992)). In some instances, patients treated with large amounts of enzymes have been prone to develop abdominal cramps (P. G. Lankisch, Digestion 37, 47-55 (1987)).
Despite efforts to delineate the role of pancreatic proteases for treatment of pain, including abdominal pain in pancreatitis, the need still exists for further therapy regimens. The present invention addresses that need.